Thee overall goal of this project is the discovery of new drugs for the treatment of acquired immune deficiency syndrome (AIDS), a devastating illness whose worldwide impact has been virtually without precedent in modem medicine. A vast amount of knowledge has been gained about the molecular biology and mode of replication and transmission of human immunodeficiency virus type I (HIV-1), the etiologic agent associated with AIDS in the U.S. However, drugs currently approved for clinical use against AD:)S and the early-stage disease called AIDS-related complex (ARC) are small in number and not without side effects. Moreover, reports of drug resistance have begun to appear. Thus, there is a compelling need for new agents to expand our therapeutic armamentarium against this disease. The present application is a consolidation of two R01 grants. The proposed research, which is an extension of both projects, can be divided into two broad areas based on our currently ongoing work: (1) antiretroviral dideoxynucleosides (ddN's) in which the heterocycle or the sugar is modified; and (2) -novel lipophilic esters of the antiretroviral drug phosphonoformic acid (PFA) in which the carboxylic or phosphonic acid group is linked to an antiretroviral ddN. The considerable progress made to date on the synthesis of these two groups of compounds provides strong momentum to continue this research. Goals to be pursued in the area of base-modified and sugar-modified ddn's include: (1) new 6-azauracil, 6-azathymine, and 6-azacytosine derivatives,e.g., the 6-aza analogs of 3'-deoxy-3'-fluorothymidine (3'-FdThd), 2',3'-didehydro-3'-deoxythymidine (D4T), and 2,3'-dideoxycytidine (D2C); (2) 2beta-fluoro derivatives of 2-chloro-2',3'-dideoxyadenosine and 2',3'deoxy-2-fluoroadenosine; and (3) 1-(3'-deoxythymidin-3'-yl) and 1-(2',3'-dideoxyuridin-3'-yl)allene, novel ddN's with an isoelectronic allene moiety occupying the azido site in AZT. Goals to be pursued in the area of PFA-ddN conjugates include analogs in which: (1) the phosphonic acid group is linked to AZT and the carboxylic acid is linked to a simple alkyl or aryl group; (2) the carboxyl group is linked to AZT and the phosphonic acid group is linked to a simple alkyl or aryl group; (3) the phosphonic or carboxylic acid group is linked to other ddN's such as D2C, 2',3'-dideoxyinosine (D21), and 3'-FdThd; and (4) the phosphonic carboxyl or group is linked to a lipid such as cholesterol or a diglyceride for targeted delivery to HIV-infected monocyte/macrophages. In vitro biological evaluation will include testing of the ability of these compounds to block HIV-1 replication in human and monkey T lymphocytes, peripheral blood leukocytes, and purified monocyte/macrophages, and of their ability to inhibit host-cell growth. 5'-Triphosphate esters of nucleosides that prove active in vitro will also be synthesized chemically and tested for the ability to competitively inhibit reverse transcriptase activity in a cell-free system. Compounds showing enough activity in vitro will be resynthesized for in vivo testing by Dr. Ruprecht as part of her active work on new anti-AIDS drugs in relevant murine models such as HIV-1 infected chimeric SCID mice.